This proposal is for molecular genetic assessment of SNCA in alpha-synucleinopathy. Our data shows alpha-synuclein overexpression is sufficient to give rise to a spectrum of Parkinsonism disorders, including Parkinson's disease, parkinsonism and dementia, dementia with Lewy bodies and multiple system atrophy; alpha-synuclein is undoubtedly a central component in sporadic and familial disease. Our aims are to: 1) identify genetic variability in the SNCA locus and determine what contribution it has to these phenotypes; 2) molecularly, clinically and pathologically characterize SNCA multiplication mutations;, 3) quantify SNCA gene expression in normal aging and disease, and; 4) functionally assess genetic variability within the gene and its promoter. Furthermore, we are to examine the transcriptional consequence of alpha-synuclein over-expression, in model systems, in human brain tissue from cases with SNCA multiplication. Our objective is to provide meaningful molecular diagnoses to reclassify this heterogeneous group of diseases, into distinct groups, for further longitudinal and pathological assessment. As alpha-synuclein has an extended half-life (approximately 30hrs), thus our work is focused on characterizing SNCA genetic variability, transcriptional regulation and mRNA expression. We posit reduction in alpha-synuclein expression may provide a powerful therapeutic strategy to prevent alpha-synucleinopathy or halt its progression.